The effects of controlling childhood asthma of the same daily dose (400 pg) of beclomethasone dipropionate, given in two or four equal divided doses from a metered aerosol, were compared in a double blind crossover study. Thirty one children aged 6-14 years completed the study. They had previously been shown to need beclomethasone by showing either symptoms or reduced peak flow when the treatment was withdrawn. They recorded their daytime and night time symptoms on a visual analogue scale and their morning and evening peak expiratory flow (PEF), and recorded their symptomatic use of bronchodilator aerosols. Spirometry was performed at the end of each treatment period. Control of asthma was good on both regimens. There were small differences in both objective and subjective measurements in favour of the four times daily regimen, but none reached statistical significance, apart from patients' assessment of daytime wheeze (p < 0-05). In particular, the differences in the results of lung function tests were very small. Compliance was better for morning and evening doses. These results suggest that beclomethasone given as 200pg twice daily is effective in controlling mild childhood asthma. It may be preferable to lOO1g four times daily because of better compliance and because it is unnecessary to take medication to school.Inhaled beclomethasone dipropionate has been used for over 10 years in the treatment of childhood asthma.' 2 During that time many accounts of its usefulness and safety have been published.34 The recommended standard dose of 100 pg (two puffs from a metered dose inhaler) four times a day has been shown to be effective in controlling symptoms and it can successfully replace oral steroid treatment in a large proportion of steroid dependent patients. This standard dose has been shown not to suppress the pituitary-adrenal axis.56 Furthermore, it does not affect linear growth7 and has no long term deleterious effect on the bronchial mucosa.8Problems with compliance are more frequent when drugs have to be taken several times a day.9 "'Treatment twice daily is easier to manage than treatment four times daily, especially in children as parental supervision can be more strict and it removes the inconvenience of having to take medication at school.
Background: Warfarin is the most commonly used oral anticoagulant, but its use is limited by the narrow therapeutic index. Single nucleotide polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) have been shown to impact warfarin dose requirements. Use of such pharmacogenetic data to improve warfarin dosing has been widely studied in adult populations and is being integrated into clinical practice. However, there remains a paucity of data on the appropriate use of this genetic information in the pediatric population. We developed a retrospective review of pediatric patients on warfarin therapy to evaluate associations between CYP2C9 and VKORC1 polymorphisms and warfarin dose requirements in children. Methods: Patients were recruited from outpatient clinics at Texas Children’s Hospital and Stollery Children’s Hospital. Any patient less than 18 years of age that had taken warfarin and achieved maintenance dose was eligible. Blood sample or buccal swab was collected for genotyping and clinical data was collected from the medical record. Genotyping was performed by melting curve analysis to detect CYP2C9*2, CYP2C9*3, or VKORC1 −1639 mutations. Warfarin genotyping reagents were obtained from Idaho Technology and assays were run using the Roche LightCyler instrument. Results: This study was initiated in March 2008 and is ongoing. To date 47 children (23M: 24F) have been enrolled. Indications for warfarin therapy include: arrhythmia (n=2), artificial heart valve (n=10), pulmonary hypertension (n=10), deep vein thrombosis (n=9), pulmonary embolism (n=2), Fontan (n=10), stroke (n=2), other (n=2). The mean age is 9.3 years (range 1–18); median target International Normalized Ratio (INR) range is 2–3 (with similar target INRs across genotypes). Twenty-nine patients have fully evaluable data at the time of this report, of whom 21 (72%) are wild type CYP2C9, 6 (21%) carry at least 1 mutant allele, and 2 (7%) are homozygous or compound heterozygote. As compared with wild type patients (mean dose 0.14mg/ kg/day), patients with heterozygous (0.09mg/kg/day; p=0.04) or homozygous (0.05mg/ kg/day; p=0.001) genotype required significantly lower maintenance daily warfarin dose. For VKORC1 −1639 genotype 6 (21%) are AA, 11 (38%) are GA, and 12 (41%) are GG. As compared with GG patients (mean dose 0.16mg/kg/day), patients with 1 (0.11mg/kg/ day; p=0.12) or 2 (0.09mg/kg/day; p=0.02) A allele required lower doses. Discussion: We present the first pediatric series to evaluate the influence of CYP2C9 and VKORC1 genotype on warfarin dosing. These data demonstrate genotype frequency similar to adults, and suggests that genotype influences the maintenance warfarin dose in children. Enrollment to this study is ongoing, and will allow a more precise evaluation of the impact of genotype and additional demographic data on pediatric dosing. These data will provide for development of a pediatric dosing algorithm to predict maintenance warfarin dose a priori.
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